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  2. First fragment-based screening identifies new chemotypes inhibiting ERAP1-metalloprotease

First fragment-based screening identifies new chemotypes inhibiting ERAP1-metalloprotease

  • Eur J Med Chem. 2024 Sep 30:280:116926. doi: 10.1016/j.ejmech.2024.116926.
Vasileios Fougiaxis 1 Valentina Barcherini 1 Milena M Petrovic 1 Pierre Sierocki 2 Sandrine Warenghem 1 Florence Leroux 2 Nour Bou Karroum 1 Fabien Petit-Cancelier 3 Vincent Rodeschini 3 Didier Roche 3 Benoit Deprez 2 Rebecca Deprez-Poulain 4
Affiliations

Affiliations

  • 1 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000, Lille, France.
  • 2 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000, Lille, France; European Genomic Institute for Diabetes, EGID, University of Lille, F-59000, France.
  • 3 Edelris, 60 avenue Rockefeller, Bioparc, Bioserra 1 Building, 69008, Lyon, France.
  • 4 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000, Lille, France; European Genomic Institute for Diabetes, EGID, University of Lille, F-59000, France. Electronic address: rebecca.deprez@univ-lille.fr.
Abstract

Inhibition of endoplasmic reticulum Aminopeptidase 1 (ERAP1) by small-molecules is being eagerly investigated for the treatment of various autoimmune diseases and in the field of immuno-oncology after its active involvement in antigen presentation and processing. Currently, ERAP1 inhibitors are at different stages of clinical development, which highlights its significance as a promising drug target. In the present work, we describe the first-ever successful identification of several ERAP1 inhibitors derived from a fragment-based screening approach. We applied an enzymatic activity assay to a large library of ∼3000 fragment entries in order to retrieve 32 hits. After a multi-faceted selection process, we prioritized 3 chemotypes for SAR optimization and strategic modifications provided 2 series (2-thienylacetic acid and rhodanine scaffolds) with improved analogues at the low micromolar range of ERAP1 inhibition. We report also evidence of selectivity against homologous Aminopeptidase IRAP, combined with complementary in silico docking studies to predict the binding mode and site of inhibition. Our compounds can be the starting point for future fragment growing and rational drug development, incorporating new chemical modalities.

Keywords

Aminopeptidases; ERAP1; Fragment-based screening; IRAP; Inhibitors.

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